The objectives of this proposal are two-fold: a) the development of a new topical product for the treatment of acne vulgaris, and b) the development of a new topical product for the treatment of premature aging of the skin caused by inflammation, PMNL activation, and keratinization disorders. The hypothesis is that infection and corresponding PMNL activation increase the level of inflammatory response in skin and induce oxidative bursts in PMNLs. The enhanced oxidative stress results in damage to the skin. The new topical product(s) will contain a fluorinated derivative of Vitamin D3, ST-630 as the active ingredient. This Phase I proposal is hoping to establish that ST-630: a) penetrates into and through human skin in vitro; b) inhibits the generation of reactive oxygen species (ROS) in keratinocytes and neutrophils (hence preventing oxidative stress); c) has antiproliferative and prodifferative activities in keratinocytes; d) inhibits the growth of P. acnes, one of the primary pathogenic factors for acne development; and, ) reduces the oxidative damage and antioxidant depletion in animals after UV irradiation. The formulations proposed are oil-in-water creams which will be designed to minimize the potential for systemic signs of hypercalcemia and the potential for local irritation. Penederm has developed a proprietary excipient, PP2 (polyolprepolymer 2, a liquid polyol, molecular weight 4000 Daltons). This ingredient has been shown to retain ST-630 within the skin and, hence, will hopefully reduce systemic accumulation of the drug. Several Vitamin D derivatives have been reported in the literature including calcitriol and calcipotriene (calcipotriol). These were observed to be effective in the treatment of psoriasis. Recently, Wiseman showed that cholecalciferol and calcitriol inhibit iron-dependent lipid peroxidation in vitro. Vitamin D3 is formed in humans by the action of sunlight on the skin, and thus, its antioxidant action should help protect the cells in which it is formed against the aging and carcinogenic effects of UV light caused in part by peroxidation of cell membranes. ST-630 is a synthetic analog of calcitriol and was found more potent than the parent compound in several assays: 10-fold in the in vitro suppression of the proliferation of human promyelocytic leukemia cells, 20-50-fold increase in the in vitro differentiation of HL-60 cells, etc. This higher activity may be due to the longer half-life of ST-630 or due to the fact that its major metabolite, ST-232, is both stable and active.